This invention concerns benzamide compounds, pharmaceutical compositions containing these compounds, and their use to treat or protect against neurodegenerative conditions.
Neurodegenerative disease encompasses a range of seriously debilitating conditions including Parkinson""s disease, amyotrophic lateral sclerosis (ALS, xe2x80x9cLou Gehrig""s diseasexe2x80x9d), multiple sclerosis, Huntington""s disease, Alzheimer""s disease, diabetic retinopathy, multi-infarct dementia, macular degeneration and the like. These conditions are characterized by a gradual but relentless worsening of the patient""s condition over time. The mechanisms and causes of these diseases are becoming better understood and a variety of treatments have been suggested. One of these neurodegenerative conditions, Parkinson""s disease, is associated with abnormal dopamine depletion in selected regions of the brain.
Recent summaries of the state of understanding of Parkinson""s disease are provided by Marsden, C. D., in xe2x80x9cReview Articlexe2x80x94Parkinson""s Diseasexe2x80x9d Lancet (Apr. 21, 1990) 948-952 and Calne, D. B., in xe2x80x9cTreatment of Parkinson""s Diseasexe2x80x9d NEJM (Sep. 30, 1993) 329:1021-1027. As these reviews point out, dopamine deficiency was identified as a key characteristic of Parkinson""s disease, and the destruction of the dopaminergic nigrostriatal pathway paralleled dopamine depletion in Parkinson""s patients.
Rapid development of Parkinson""s-like symptoms in a small population of illicit drug users in the San Jose, Calif. area was linked to trace amounts of a toxic impurity in the home-synthesized drugs. Subsequent studies in animal models, including monkeys, demonstrated that 1-methyl-4-phenyl-1, 2,5,6-tetrahydropyridine (MPTP) was the cause of the Parkinson""s-like symptoms which developed in the illicit drug users, as reported by J. W. Langston et al., in xe2x80x9cChronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesisxe2x80x9d Science (Feb. 25, 1983) 219, 979-980. These early findings and the many studies that they stimulated led to the development of reliable models for Parkinson""s disease, as reported by Heikkila, R. E., et al., in xe2x80x9cDopaminergic Neurotoxicity of 1-Methyl-4-Phenyl-1, 2,5,6-Tetrahydropyridine in Micexe2x80x9d Science (Jun. 29, 1984) 224:1451-1453; Burns, R. S., et al, in xe2x80x9cA Primate Model of Parkinsonism. . . xe2x80x9d Proc. Natl. Acad. Sci USA (1983) 80:4546-4550; Singer, T. P., et al., xe2x80x9cBiochemical Events in the Development of Parkinsonism. . .xe2x80x9d J. Neurochem. (1987) 1-8; and Gerlach, M. et al., xe2x80x9cMPTP Mechanisms of Neurotoxicity and the Implications for Parkinson""s Diseasexe2x80x9d European Journal of Pharmacology (1991) 208:273-286. These references and others describe studies to help explain the mechanism of how the administration of MPTP to animals gives rise to motor defects characteristic of Parkinson""s disease. They clearly indicate that MPTP was the cause of the Parkinson""s-like symptoms that developed in the humans who had used the tainted illicit drugs and that similar motor deficits were found in other primates and other test animals which had been dosed directly with MPTP. They further point out that the administration of MPTP induces a marked reduction in the concentration of dopamine in the test subjects.
These findings have led to the development of an assay for agents effective in treating dopamine-associated neurodegenerative disorders, such as Parkinson""s disease. In this assay, test animals are given an amount of MPTP adequate to severely depress their dopamine levels. Test compounds are administered to determine if they are capable of preventing the loss of dopamine in the test animals. To the extent that dopamine levels are retained, a compound can be considered to be an effective agent for slowing or delaying the course of neurodegenerative disease, e.g., Parkinson""s disease.
Mitochondrial function is associated with many neurodegenerative diseases such as ALS, Huntington""s disease, Alzheimer""s disease, cerebellar degeneration, and aging itself (Beal, M. F. in Mitochondrial Dysfunction and Oxidative Damage in Neurodegenerative Diseases, R. G. Landes Publications Austin, Tex., 1995 at, for example, pages 53-61 and 73-99). Mitochondrial damage is the mechanism by which MPTP depletes dopamine concentrations in the striatum (Mizuno, Y., Mori, H., Kondo, T. in xe2x80x9cPotential of Neuroprotective Therapy in Parkinson""s Diseasexe2x80x9d CNS Drugs (1994) 1:45-46). Thus, an agent which protects from mitochondrial dysfunction caused by MPTP could be useful in treating diseases of the central nervous system in which the underlying cause is mitochondrial dysfunction.
While other benzamide compounds are known, their utility heretofore has generally been as intermediates in chemical syntheses or in fields unrelated to the present invention. Slight structural changes yielded large differences in efficacy and toxicity. The vast majority of benzamide compounds have little or no activity in our screens. However, there are reports of biological activity for other, structurally different benzamides. These reports include:
El Tayar et al., xe2x80x9cInteraction of neuroleptic drugs with rat striatal D-1 and D-2 dopamine receptors: a quantitative structurexe2x80x94affinity relationship studyxe2x80x9d Eur. J. Med. Chem. (1988) 23:173-182;
Monkovixc4x87 et al., xe2x80x9cPotential non-dopaminergic gastrointestinal prokinetic agents in the series of substituted benzamidesxe2x80x9d Eur. J. Med. Chem. (1989) 24:233-240;
Banasik et al., xe2x80x9cSpecific inhibitors of poly(ADP-Ribose) synthetase and mono(ADP-ribosyl)transferasexe2x80x9d J. Biol. Chem. (1992) 267:1569-1575;
Bishop et al., xe2x80x9cSynthesis and in vitro evaluation of 2,3-dimethoxy-5-(fluoroalkyl)-substituted benzamides: high-affinity ligands for CNS dopamine D2 receptorsxe2x80x9d J. Med. Chem. (1991) 34:1612-1624;
Hxc3x6gberg et al., xe2x80x9cPotential antipsychotic agents. 9. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class of substituted (R)-N-[benzyl-2-pyrrolidinyl)methyl]benzamides. Relations to other side chain congenersxe2x80x9d J. Med. Chem. (1991) 34:948-955;
Katopodis et al., xe2x80x9cNovel substrates and inhibitors of peptidylglycine xcex1-xcex1-amidating monooxygenasexe2x80x9d Biochemistry (1990) 22:4541-4548; and
Rainnie et al., xe2x80x9cAdenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousalxe2x80x9d Science (1994) 263:689-690.
Other benzamide-containing pharmaceutical compositions and their use to treat or protect against neurodegenerative conditions were disclosed in commonly owned U.S. patent application Ser. No. 08/227,777 filed Apr. 14, 1994, the disclosure of which is incorporated herein by reference in its entirety.
It has now been found that a family of novel acetamidobenzamide compounds of the Formula I below exhibit strong activity against Parkinson""s disease as measured by their ability to prevent MPTP-induced reduction of dopamine levels. 
where Rxe2x80x2 is a straight, branched or cyclic saturated all of from 3 to 5 carbon atoms and n is 1 or 2.
It has also been found that the novel nitro- and aminobenzamide compounds N-tert-amyl-4-nitrobenzamide (CPI1033), N-1,2-dimethylpropyl-4-nitrobenzamide (CPI1085), N-n-butyl-3-nitrobenzamide (CPI1135), N-n-pentyl-4-nitrobenzamide (CPI1140), N-2-methylbutyl-4-nitrobenzamide (CPI1146), N-n-butyl-3, 5-dinitrobenzamide (CPI1147), N-methylcyclopropyl-4-nitrobenzamide (CPI1164), N-n-butyl-2-nitrobenzamide (CPI1173), N-n-pentyl-2-nitrobenzamide (CPI1174), and N-methylcyclopropyl-4-aminobenzamide (CPI1240) are useful as intermediates for preparing the acetamide compounds of Formula I above and as pharmaceutical agents.
These nitro- and aminobenzamide compounds and the acetamidobenzamide compounds of Formula I constitute one aspect of the invention.
The invention can also take the form of pharmaceutical compositions based on one or more of the compounds of Formula II below: 
where Rxe2x80x2 is a saturated alkyl of from 3 to 5 carbon atoms, each R is independently xe2x80x94NHxe2x80x94COxe2x80x94CH3, xe2x80x94NO2 or xe2x80x94NH2, and n is 1 or 2, with the following provisos: 1) when n is 1 and R is xe2x80x94NO2 at the 4 position of the ring, Rxe2x80x2 is not tert-butyl, iso-butyl, or propyl; 2) when n is 1 and R is xe2x80x94NO2 at the 2 position of the ring, Rxe2x80x2 is not iso-butyl or propyl; and 3) when n is 2 and Rxe2x80x2 is tert-butyl and both Rs are xe2x80x94NO2, the R groups are not at the 3 and 5 positions of the ring.
The invention can further take the form of methods of treating neurodegenerative conditions using these materials.
Thus, in one aspect this invention provides the novel acetamidobenzamide compounds of the Formula I and the novel nitro- and aminobenzamides described above.
In another aspect this invention provides pharmaceutical compositions which include one or more benzamide compounds of the Formula II in a pharmaceutically acceptable carrier. This carrier is preferably an oral carrier but can be an injectable carrier as well. These pharmaceutical compositions can be in bulk form but more typically are presented in unit dosage form.
In another aspect this invention provides a method for treating a patient suffering from a dopamine-associated neurodegenerative condition. This method involves administering to the patient an effective neurodegenerative condition-treating amount of one or more of the pharmaceutical compositions just described.
In another aspect this invention provides a method for treating a patient suffering from a condition characterized by progressive loss of central nervous system function. This method involves administering to the patient with loss of central nervous system function an effective amount of one or more of the pharmaceutical compositions just described.
In a most important aspect this invention provides a method for treating a patient suffering from a progressive loss of central nervous system function associated with Parkinson""s disease. This method involves administering (preferably orally) to the patient with loss of progressive central nervous system function an effective amount of one or more of the pharmaceutical compositions just described.
In another aspect this invention provides a method for treating a patient suffering from a condition characterized by progressive loss of nervous system function due to mitochondrial dysfunction. This method involves administering to the patient with loss of central nervous system function an effective amount of one or more of the pharmaceutical compositions just described.
In a further aspect, this invention provides methods for preparing the compounds of Formula I and II. These methods generally involve condensing an alkyl amine of from 3 to 5 carbon atoms with a mono or dinitro benzoyl halide having the nitro configuration corresponding to the nitro, amine or acetamide substitution desired in the final compound, optionally, reducing the nitro groups, and, optionally, converting the amino benzamides to acetoamidobenzamides by reaction with an acetylhalide.
The Compounds
This invention provides novel acetamidobenzamide compounds of the Formula I below and their use as active pharmaceutical agents. 
where Rxe2x80x2 is a saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2.
The acetamido group may be found anywhere on the ring. Preferred embodiments include when n is 1 and the R group is at the 2, 3 or 4 position of the ring and when n is 2 and the R groups are at the 2 and 3, 2 and 4, 2 and 5, 2 and 6, 3 and 4, or 3 and 5 positions of the ring.
With respect to the alkyl substituents, compounds wherein Rxe2x80x2 is an alkyl which does not have a hydrogen on the alpha carbon, that is, the carbon which bonds to the nitrogen of the ring, are preferred. Examples of these preferred Rxe2x80x2 groups are tert-butyl and tert-amyl.
The benzamide of the Formula I above which is N-tert-butyl4-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1189.
The benzamide of the Formula I above which is N-iso-propyl-4-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1232.
The benzamide of the Formula I above which is N-tert-amyl-4-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1233.
The benzamide of the Formula I above which is N-tert-butyl-3-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1234.
The benzamide of the Formula I above which is N-methylcyclopropyl-4-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1241.
The compounds N-tert-butyl 4-acetamidobenzamide (CPI1189), N-iso-propyl-4-acetamidobenzamide (CPI1232), N-tert-amyl-4-acetamidobenzamide CPI1233), N-tert-butyl-3-acetamidobenzamide (CPI1234), and N-methylcyclopropyl-4-acetamidobenzamide (CPI1241) are the most preferred compounds of the Formula I at this time.
The invention also provides the following novel nitro- and aminobenzamide compounds which are useful both as intermediates in preparing the compounds of the Formula I and as active pharmaceutical agents: N-tert-amyl-4-nitrobenzamide (CPI1033), N-1,2-dimethylpropyl-4-nitrobenzamide (CPI1085), N-n-butyl-3-nitrobenzamide (CPI1135), N-n-pentyl-4-nitrobenzamide (CPI1140), N-2-methylbutyl-4-nitrobenzamide (CPI1146), N-n-butyl-3, 5-dinitrobenzamide (CPI1147), N-methylcyclopropyl-4-nitrobenzamide (CPI1164), N-n-butyl-2-nitrobenzamide (CPI1173), N-n-pentyl-2-nitrobenzamide (CPI1174), and N-methylcyclopropyl-4-aminobenzamide (CPI1240).
The benzamide which is N-tert-amyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1033.
The benzamide which is N-1,2-dimethylpropyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1085.
The benzamide which is N-n-butyl-3-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1135.
The benzamide which is N-n-pentyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1140.
The benzamide which is N-2-methylbutyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1146.
The benzamide which is N-n-butyl-3,5-dinitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1147.
The benzamide which is N-methylcyclopropyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1164.
The benzamide which is N-n-butyl-2-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1173.
The benzamide which is N-n-pentyl-2-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1174.
The benzamide which is N-methylcyclopropyl-4-aminobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI11240.
When the benzamide compound contains an amino group, such as CPI 1240, this functionality can be present as such or as a pharmaceutically acceptable salt. When these xe2x80x9ccompoundsxe2x80x9d are referred to it is to be understood that these salts are included as well.
Commonly owned U.S. patent application Ser. No. 08/227,777, referred to above, discloses several benzamides useful in treating neurodegenerative diseases based on their protective action in the MPTP mouse model of Parkinson""s disease. The compound N-tert-butyl 4-acetamidobenzamide (CPI1189) of the present invention is an in vivo biotransformation product of one of these benzamides (N-tert-butyl 4-nitrobenzamide (CPI1020)) which is found in the blood of rats and mice to which CPI1020 has been administered orally. This compound is likely formed in the body by reduction of the ring nitro of CPI1020 to an amino moiety (CPI1160) followed by acetylation of the amino function.
The compounds of the present invention, as exemplified by CPI1189, are much more potent than CPI1020 (approximately 10 times as potent) in protecting mice from dopamine reduction in the striatum induced by s.c. treatment with MPTP. Based on structurally similar molecules such as acetaminophen which contain an acetamido functionality, they should also be safer than CPI1020 because they would not be metabolized in the body to result in metabolites containing hydroxylamines (likely to be Ames positive) nor would they be likely to result in amino metabolites which may have cardiovascular and/or anorexic effects.
Pharmaceutical Compositions
The benzamide compounds of the Formula II below: 
where Rxe2x80x2 is a straight or branched chain saturated alkyl of from 3 to 5 carbon atoms, each R is independently xe2x80x94NHxe2x80x94COxe2x80x94CH3, xe2x80x94NO or xe2x80x94NH2, and n is 1 or 2, with the following provisos: 1) when n is 1 and R is xe2x80x94NO2 at the 4 position of the ring, Rxe2x80x2 is not tert-butyl, iso-butyl, or propyl; 2) when n is 1 and R is xe2x80x94NO2 at the 2 position of the ring, Rxe2x80x2 is not iso-butyl or propyl; and 3) when n is 2 and Rxe2x80x2 is tert-butyl and both Rs are xe2x80x94NO2, the R groups are not at the 3 and 5 positions of the ring, are formulated into pharmaceutical compositions suitable for oral or other appropriate routes of administration.
The benzamide of the Formula II above which is N-iso-propyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1026.
The benzamide of the Formula II above which is N-tert-butyl-3-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1034.
The benzamide of the Formula II above which is N-tert-butyl-2-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1035.
The benzamide of the Formula II above which is N-n-butyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1045.
The benzamide of the Formula II above which is N-n-propyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1047.
The benzamide of the Formula II above which is N-tert-butyl-3,5-dinitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1049.
The benzamide of the Formula II above which is N-1-methylpropyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1084.
The benzamide of the Formula II above which is N-tert-butyl-4-aminobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1160.
The benzamide of the Formula II above which is N-tert-butyl-3-aminobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1248.
When R is xe2x80x94NH2, the compounds of the Formula II may be used as salts in which the amine group is protonated to the cation form, in combination with a pharmaceutically acceptable anion, such as chloride, bromide, iodide, hydroxyl, nitrate, sulfonate, methane sulfonate, acetate, tartrate, oxalate, succinate, or palmoate.
Pharmaceutical compositions using the compounds N-tert-butyl 4-acetamidobenzamide (CPI1189), N-tert-butyl-3-acetamidobenzamide (CPI1234), N-tert-amyl-4-acetamidobenzamide (CPI1233), N-tert-butyl-4-aminobenzamide (CPI1160), N-tert-butyl-3-nitrobenzamide (CPI1034), and N-tert-butyl-3-aminobenzamide (CPI1248) are most preferred at this time.
The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in a unit dosage form to facilitate accurate dosing. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the benzamide compound is usually a minor component (0.1 to say 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. A liquid form may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
A solid form may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
In the case of injectable compositions, they are commonly based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. Again the active benzamide is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
These components for orally administrable or injectable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington""s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated by reference.
One can also administer the compounds of the invention in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in the incorporated materials in Remington""s Pharmaceutical Sciences. 
Conditions Treated and Treatment Regimens
The conditions treated with the benzamide-containing pharmaceutical compositions may be classed generally as neurodegenerative conditions. These include conditions characterized by protracted low grade stress upon the central nervous system and gradual progressive loss of central nervous system function. These conditions include Parkinson""s disease, amyotrophic lateral sclerosis (ALS, xe2x80x9cLou Gehrig""s diseasexe2x80x9d), multiple sclerosis, Huntington""s disease, Alzheimer""s disease, diabetic retinopathy, multi-infarct dementia, macular degeneration and the like. Each of these conditions is characterized by a progressive loss of function. The benzamide compound-containing pharmaceutical compositions of this invention, when administered orally or by injection such as intravenously, can slow and delay and possibly even to some extent reverse the loss of function.
Injection dose levels for treating these conditions range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
With these neurodegenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 1 to about 20 mg/kg of benzamide, with preferred doses each providing from about 1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
Of course, one can administer the benzamide compound as the sole active agent or one can administer it in combination with other agents, including other active benzamide compounds.
Methods of Preparation of Compounds
The benzamide compounds of this invention can be prepared using commonly available starting materials and readily achievable reactions.
One representative preparation route, which is illustrated with tert-butyl amine, but which may be used with any alkyl amine, involves the following reactions: 
where X is halo such as I, Br, F or Cl. 
In step (A) the N-tert-butyl nitrobenzamides (III) are formed. This reaction must be carried out at temperatures below 10xc2x0 C.
This step (A) yields as benzamides III, the compounds of the invention where R is xe2x80x94NO2.
In step (B) the nitro groups in the mono- or di-nitro benzamide III are subjected to reduction. This is commonly carried out with a reducing agent such as hydrazine and an appropriate catalyst such as a heterogeneous platinum, iron oxide hydroxide, palladium or nickel catalyst, typically on a support, or with hydrogen gas and a catalyst.
This step (B) yields as benzamides IV, the compounds of the invention where R is NH2.
In step (C) the amino-benzamides IV are converted to acetamidobenzamides V by reaction with an acetyl halide such as acetylchloride. This reaction is carried out in the presence of a mild base and at low to ambient temperatures such as xe2x88x9220xc2x0 C. to +20xc2x0 C. This yields the compounds of the invention where R is acetamido.
Alternate synthetic schemes may also be used to prepare the compounds of the present invention. Examples of these alternate routes are set forth below using CPI1189 as the representative compound. Other compounds may be prepared using these alternate methods by starting with appropriate starting materials, such as 2- or 3- amino- or nitro-benzonitrile or 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- diamino- or dinitro-benzonitrile and the appropriate alcohol (Alternate Route 1) or similarly substituted toluene compounds and the appropriate alkyl amine (Alternate Route 3).
Alternate Route 1
This route begins with acetylation of, for example, 4-aminobenzonitrile (A) to compound (B) using standard methods. Acid hydrolysis of tert-butanol in the presence of 4-acetamidobenzonitrile (B), provides a feasible synthetic pathway to CPI1189.
Alternate Route 2
Acetylation, using standard methods, of the inexpensive starting material PABA (C) affords a cheap method to produce 4-acetamidobenzoic acid (D). Conversion of (D) to the acid chloride (E) using standard methods (e.g., SOCl2) and subsequent amidation using standard methods, such as those described previously, produces CPI1189 from inexpensive raw materials. 
Alternate Route 3
Another method for the preparation of the compounds of the present invention begins with acetylation, using standard methods, of, for example, paratoluidine (F) to 4-acetamidotoluene (G). The synthetic intermediate (G) may be converted to 4-acetamidobenzoic acid (D) with common oxidizing agents (e.g., KMnO4) and subsequently transformed to CPI1189 as outlined in Alternate Route 2. 